Marfan Syndrome Marfan syndrome is a connective tissue disorder caused by a mutation in the fibrillin- 1 gene (FBN1) located on chromosome 15 (15q21.1). This gene encodes a glycoprotein called fibrillin- 1 which is essential for connective tissue formation. Marfan syndrome affects approximately two to three per 10 000 individuals. It is usually inherited in an autosomal dominant pattern although ap proximately 25% of affected individuals have a de novo mutation. The most serious abnormality associated with this syndrome is dilatation of the aorta which can lead to aortic dissection and rupture, a fatal condition. Other clinical features include ectopia lentis, scoliosis, crowded teeth as well as flexible and painful joints. Children with Marfan syndrome may grow extremely tall with especially long arms, legs, fingers, and toes. In 1986, an expert panel developed a set of diagnostic criteria, called the Berlin nosology, aimed to facilitate accurate diagnosis. This was later revised due to overdiagnosis and the commonly used Ghent criteria were developed, with further revisions in 2010. These diagnostic criteria are mainly focused on the family history of Marfan, ectopia lentis, aortic dila tation, and FBN- 1 mutations. Additional criteria include body dis proportions and musculoskeletal abnormalities.
Loeys– Dietz Syndrome
Loeys– Dietz syndrome is an autosomal dominant genetic disorder affecting the collagen production in the connective tissue caused by a mutation of the transforming growth beta signalling pathway. It has similarities to Marfan syndrome such as an increased risk of aorta dissection due to an aneurysm. Other clinical features beside overgrowth are hypertelorism and cleft palate.
Homocystinuria
Homocystinuria is an autosomal recessive disorder caused by a mutation in the cystathionine- beta- synthase (CBS) gene on chromosome 21 (21q22.3) affecting approximately one in 6000 newborn children. Individuals with homocystinuria have a deficient elimination of homocysteine and its metabolites. There are two types, B6- responsive and B6- nonresponsive homocystinuria, the first usually being milder than the second. Homocystinuria affects connective tissues in the body, including fibrillin. Affected individuals may exhibit clinical features similar to those in Marfan syndrome including tall stature with long legs and arms, scoliosis, and ectopia lentis. They might also suffer developmental delay (especially the B6- nonresponsive type) and thromboembolic complications which can lead to an early death.
Multiple Endocrine Neoplasia Type 2B
Another differential diagnosis in patients with Marfanoid habitus is multiple endocrine neoplasia type 2B (MEN2B) which is a rare autosomal dominant disorder caused by mutations in the RET gene. Clinical manifestations include mucosal neuromas on the tongue, lips, oral cavity, and conjunctivae which are white- yellow papules a few millimetre in size and may be present at birth and can usually be found by age 10 years. Gastrointestinal complaints caused by diffuse gastrointestinal ganglioneuromatosis may be present from infancy or early childhood. Affected individuals are at high risk of developing medullary thyroid cancer at a very young age and have an increased risk of pheochromocytoma.
Klinefelter Syndrome
Klinefelter syndrome, also called 47,XXY, affects one to two boys per 1000. Due to an extra X- chromosome, these patients have excess expression of certain genes. One of these is the short stature homeobox (SHOX) gene, which has been shown to influence the phenotype seen in Klinefelter syndrome. Clinical features include tall stature, small external genitalia, muscle weakness, cognitive disabilities, behavioural problems, infertility, and gynecomastia. Affected boys also have a higher risk of developing diabetes mellitus, cancer, and cardiovascular disease. Klinefelter syndrome is often diagnosed late, when affected men fail to conceive.
Fragile X
Fragile X affects approximately one in 5000 males and one in 10 000 females and is caused by a mutation in the fragile X mental retardation 1 (FMR1) gene located on the X- chromosome. Symptoms include tall stature, intellectual disability, developmental delay, autism and a characteristic appearance with a protruding forehead, and large ears.
Sotos Syndrome
Sotos syndrome affects one in 10 000 to 14 000 newborns and is caused by mutations in the nuclear receptor binding SET domain protein 1 (NSD1) gene in 90% of the cases. The skull is large and affected individuals have an increased height velocity during the first 4 years of life and an increased adult height. Cognitive disabilities are common.
Nevo Syndrome
Nevo syndrome is caused by a NSD1 deletion and is inherited in an autosomal recessive pattern. It shares clinical features with the more common Sotos syndrome described earlier.
Weaver Syndrome
Mutations in the oncogene EZH2 causes Weaver syndrome which is associated with tall stature, dysmorphic facial features, and learning difficulties. Due to the similar clinical picture it is often mis taken for Sotos syndrome.
Trisomy X
Trisomy X is a sex chromosome aneuploidy affecting approximately 1 in 1000 girls. It is associated with tall stature as well as behavioural problems and learning difficulties.
Simpson– Golabi– Behmel Syndrome
The overgrowth condition Simpson– Golabi– Behmel syndrome (SGBS) is caused by a mutation in the X- linked SGBS gene. In addition to tall stature affected individuals may exhibit supernumerary nipples, muscular hypotonia and an increased risk of tumours in infancy has been seen.
Beckwith– Wiedemann Syndrome
Most affected individuals with Beckwith– Wiedemann syndrome (BWS) have an imprinting disorder of one or two gene clusters that contain the IGF2 and H19 genes, under control of chromosome 15 imprinting centre 1 (IC1), and the CDKN1C and KCNQ1OT1 genes, under control of imprinting centre 2 (IC2). Approximately 65% of children with BWS have a birth weight above the 90th percentile. They are tall in childhood and mean adult height has been reported to be 1.8 ± 1.2 SDS above normal. Congenital anomalies such as macroglossia, ear creases or pits, naevus flammeus, and abdominal wall defects are characteristic of BWS as is hemihyperplasia. Affected individuals may develop hypoglycaemia due to hyperinsulinism in the neonatal period and also have an increased risk of developing embryonic tumours, especially Wilms tumour.
PTEN Hamartoma Tumour Syndromes
This group of growth disorders includes Cowden disease and Bannayan– Riley– Ruvalcaba syndrome and affects approximately one in 200 000– 250 000. They are caused by a mutation of the PTEN tumour suppressor genes and are inherited in an autosomal dominant pattern.
Perlman Syndrome
Perlman syndrome is a rare autosomal recessive genetic disorder caused by a mutation in the DIS3L2 gene. It is characterized by overgrowth, dysmorphic facial features, renal dysplasia, and an increased risk of developing Wilms tumour. It has a poor prognosis with a high neonatal mortality.
